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Novel Scaffold Identification of mG lu1 Receptor Negative Allosteric Modulators Using a Hierarchical Virtual Screening Approach
Author(s) -
Jang Jae Wan,
Cho NamChul,
Min SunJoon,
Cho Yong Seo,
Park Ki Duk,
Seo Seon Hee,
No Kyoung Tai,
Pae Ae Nim
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12654
Subject(s) - virtual screening , pharmacophore , g protein coupled receptor , allosteric regulation , rhodopsin , computational biology , homology modeling , metabotropic glutamate receptor 1 , metabotropic glutamate receptor , biology , chemistry , bioinformatics , biochemistry , receptor , glutamate receptor , retinal , enzyme
Metabotropic glutamate receptor 1 ( mG luR1) is considered as an attractive drug target for neuropathic pain treatments. The hierarchical virtual screening approach for identifying novel scaffolds of mG luR1 allosteric modulators was performed using a homology model built with the dopamine D3 crystal structure as template. The mG luR1 mutagenesis data, conserved amino acid sequences across class A and class C GPCR s, and previously reported multiple sequence alignments of class C GPCR s to the rhodopsin template, were employed for the sequence alignment to overcome difficulties of model generation with low sequence identity of mG luR1 and dopamine D3. The structures refined by molecular dynamics simulations were employed for docking of Asinex commercial libraries after hierarchical virtual screening with pharmacophore and naïve Bayesian models. Five of 35 compounds experimentally evaluated using a calcium mobilization assay exhibited micromolar activities ( IC 50) with chemotype novelty that demonstrated the validity of our methods. A hierarchical structure and ligand‐based virtual screening approach with homology model of class C GPCR based on dopamine D3 class A GPCR structure was successfully performed and applied to discover novel negative mG luR1 allosteric modulators.